Catalytic Electrophilic Halogenation of Arenes with Electron-Withdrawing Substituents

Abstract

The electrophilic halogenation of arenes is perhaps the simplest method to prepare aryl halides, which are important structural motifs in agrochemicals, materials, and pharmaceuticals. However, the nucleophilicity of arenes is weakened by the electron-withdrawing substituents, whose electrophilic halogenation reactions usually require harsh conditions and lead to limited substrate scopes and applications. Therefore, the halogenation of arenes containing electron-withdrawing groups (EWGs) and complex bioactive compounds under mild conditions has been a long-standing challenge. Herein, we describe Brønsted acid-catalyzed halogenation of arenes with electron-withdrawing substituents under mild conditions, providing an efficient protocol for aryl halides. The hydrogen bonding of Brønsted acid with the protic solvent 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP) enables this transformation and thus solves this long-standing problem.

Synthesis, structural characterization, reactivity and catalytic activity of mixed halo/triflate ArI(OTf)(X) species

“…Jiao and coworkers have recently reported the combination of HOTf and TCICA in hexafluoro isopropanol (HFIP) at 60 °C. 40 Comparing these systems, the chlorinating ability is similar to ours, with similar levels of HOTf being used to catalyse both systems. We do however note that our systems are performed in chloroform, whereas HFIP is conditional for their system.…”

“…With the hypothesis that I5 is an active chlorinating reagent and a more powerful chlorinating agent than Cl2 itself, its activity was screened via direct reaction against a range of deactivated aryl substrates as well as by catalytic activation of I4. It is common practice to observe and report the yields of EAS reactions by analysis of reactions mixtures with GC-MS or NMR analysis; [39][40][41][42] here in situ NMR yields are reported using NO2-PhI as the internal standard to obtain results representative of system reactivity and regioisomer distribution.…”

“…We do however note that our systems are performed in chloroform, whereas HFIP is conditional for their system. 40 TCICA has also been activated by other means. This includes using 98% H2SO4 as the reaction media at elevated temperatures, this system was able to chlorinate highly deactivated substrates in nitrobenzene and m-dinitrobenzene in respectable yields, 44 though H2SO4 is potentially disadvantageous as a reaction media due to its corrosivity.…”

N-Haloimide-enabled halogenationviahalogen-bond-assisted C–C activation of alkanols

“…In the case of N -haloimides, a type of bench-stable and commercially available halogen sources in electrophilic halogenation reactions, 13 it is commonly recognized that the anisotropic electrostatic potential from the electron density redistribution of the halogen atom can form a σ-hole, which undergoes linear interaction with N -, O -nucleophiles to form a halogen bond (Scheme 1b). 14 Inspired by the formation of reactive hypobromites driven by halogen bonding interaction of phenols and NBS, 15 we wondered whether analogous hypohalites could be generated in situ through a photo-excited halogen bonding complex generated from alkanol and N -haloimide.…”

Concise Total Synthesis of Salimabromide

“…This hypothesis was supported by preliminary experimental studies . Finally, dibromination by utilizing the Brønsted acid-catalyzed halogenation of arenes recently disclosed by Jiao and co-workers was found to be superior to Magauer’s protocol and provided salimabromide in a better yield …”